Soldiers in the war zone are at high risk for potentially significant repercussions resulting from combat experiences. Combat stress can lead to a number of highly impactful emotional and cognitive conditions, most notably Posttraumatic Stress Disorder (PTSD), Major Depressive Disorder (MDD), and mild Traumatic Brain Injury (mTBI). The primary goal of affective neuroscience is to effectively identify the neural substrates that define mental disorders. While cross-sectional brain imaging research has provided enormous insight into the mechanisms of major mental disorders, these conditions are by nature dynamic and a snapshot of the turbulence of these conditions provides a limited methodology for understanding how changes in symptoms are reflected in the underlying brain mechanisms. Our application attempts to use an approach that maps these dynamic conditions over time using 3 sessions spaced 9 month apart to measure the dynamics in brain processing in Veterans with significant combat exposure. This approach will enable a better understanding of the fluctuation and dynamics of the neural systems involved in PTSD, in the context of MDD and mTBI. Functional magnetic resonance imaging (fMRI) allows for measurement of the hemodynamic brain response during specific processes, such as anticipation of aversive stimuli, which are relevant to the pathophysiology of PTSD. The goal of this application is to determine the brain mechanisms that delineate PTSD and determine how these mechanisms can predict poor clinical course. We posit that measurement of the dynamic change in brain response to anticipatory stress can incorporate the fluctuations clinical course of PTSD, MDD, and mTBI. Conversely, these fluctuations often obscure understanding of brain processing when assessed cross-sectionally. We will examine this hypothesis by pursuing the following three specific aims: (1) Identify cross- sectionally neural biomarkers of combat-related PTSD and determine if these biomarkers are sufficiently sensitive and specific; (2) Determine the extent to which brain activation to anticipatory stress at baseline predicts changes in PTSD symptom severity at follow-up and (3) Determine the extent to which specific candidate neural biomarkers reflect the clinical course of PTSD and key comorbid disorders and how these regions differentially recruit modulatory networks. In the short term, this research may contribute to the development of well-developed neural models of these disorders in our Veteran population. In the long term, this research will lay the foundation for studies aimed at determining candidate neural biomarkers that can provide an objective neural representation of disease course for therapeutic intervention studies.